Ionic Liquids-Assisted Ring Opening of Three-Membered Heterocycles with Thio- and Seleno-Silanes

Abstract

Ring opening reactions of strained heterocycles (epoxides, aziridines, thiiranes) by silyl chalcogenides, such as thiosilanes and selenosilanes, can be efficiently performed in a variety of ionic liquids, which can behave as reaction media and in some cases also as catalysts. This protocol enables an alternative access to β-functionalized sulfides and selenides under mild conditions.

1. Introduction

The important role played by organic derivatives of sulfur is well known in numerous fields. Sulfur-containing groups find application in organic chemistry and in a wide range of pharmaceuticals [1,2], foods [3,4], natural compounds [5] and materials [6]. Among the wide variety of sulfurated compounds, β-hydroxy sulfides represent an important class of molecules present in natural products such as, for example, leukotrienes and pteriatoxin A. β-Hydroxy sulfides [7,8] are also used for clinical applications in the treatment of various diseases, i.e., heart diseases and hypertension (diltiazem). Catalyzed addition reactions to alkenes or thiolysis of epoxides with thiols or disulfides are the more common methodologies to obtain β-hydroxy sulfides [9,10,11,12]. Furthermore, the versatility of silyl nucleophiles as alternative reagents to corresponding proton nucleophiles has been well established [13]. In this context, organothiosilanes are used as synthetic equivalents of thiols for the delivery of sulfurated moieties under milder conditions [14,15,16,17,18]. On this matter, we have reported the tetrabutylammonium fluoride (TBAF) and tetrabutyl-ammonium phenoxide (PhONⁿBu₄) catalyzed ring opening reactions of strained heterocycles upon treatment with thiosilanes [15] and, more recently with selenosilanes [19,20], to prepare sulfides, thiols, selenides, diselenides and selenols with hydroxyl, amino and mercapto moieties on the β-position. These bifunctionalized compounds represent a class of useful synthons, serving as building blocks to prepare more complex molecules. Thus, the search for new methodologies to access these compounds is still ongoing, and the development of environmentally friendly protocols is of particular and significant interest. The ionic liquids (ILs) have attracted great attention as alternative reaction media to reduce the application of volatile organic solvents [21,22,23,24,25]. Room temperature ionic liquids (RTILs) are liquids over a wide range of temperatures. RTILs possess valuable properties, such as negligible vapor pressure, thermal and chemical stability, non-inflammability, efficient solvating ability towards organic and inorganic compounds, and recyclability. Additionally, some ionic liquids have demonstrated a catalytic activity towards a variety of organic reactions [26,27,28,29,30,31], such as, for example, [emim][dcn], [bmim][BF₄], [bmim][PF₆], [bmim][Cl], [bmim][SnCl₃], and [bmim][PTSA]. ILs are composed of positive and negative ions, whose nature allows the tuning of ionic liquids properties; due to this ability, they are defined as “designer solvents”.

Ionic liquids comprising stable anion like fap (fap = tris(pentafluoroethyl)trifluoro-phosphate, [(C₂F₅)₃PF₃]) or triflate and cation (such as bmpl = 1-butyl-1-methylpyrrolidinium) have proved to be a useful medium for reactions with aggressive and dangerous reagents, for instance with elemental fluorine F₂ [32], SF₄ [33] and NaN₃ and HN₃ [34]. Ionic liquids can serve not only as reaction mediums but also as catalysts to promote various reactions [35]. In particular, ILs with [HSO₄]-anion, which possess a certain Brønsted acidity, have been found to be an advanced medium for dehydration of alcohols [36]. For example, 1-phenylcyclox-1-ene can be obtained in high yield by heating (80–90 °C, for 1 h) of the 1-phenyl-cyclohexan-1-ol in 1-ethyl-3-methyl-imidazolium hydrogensulfate, [emim][HSO₄]. Ionic liquids can be regenerated and reused several times without losing their activity in this reaction. IL [emim][HSO₄] has been successfully used for the conversion of mono-, di-, and polysaccharides into furan derivatives, for instance xylose into furfural, or fructose and polysaccharide Inulin into 5-(hydroxymethyl)-2-furaldehyde [37]. The dehydration of primary alcohols requires stronger acidic conditions, which can be achieved by addition of the corresponding acid to ionic liquid. For instance, ionic liquid + Brønsted acid, i.e., [emim][HSO₄] + concentrated sulfuric acid, [emim][CF₃SO₃] + Triflic acid, and [emim][CF₃C(O)O] + trifluoroacetic acid have been successfully used for the conversion of hexan-1-ol into dihexyl ether, cyclohexanol into cyclohexene, and tert-butanol into iso-butylene [36]. It is interesting to note that Brønsted acid, added to an ionic liquid with the same counter anion, does not evaporate from this mixture even at a temperature well above the boiling point of pure Brønsted acid [35]. An acidic system of ionic liquid and Brønsted acid can be used to carry out cascade reactions. For example, the reaction of 4-brom-3,5-dimethyl-phenol and buten-2-ol in a two-phase system, [emim][HSO₄] + H₂SO₄/Hexane, proceeds at low temperature (55–60 °C) and results in the formation of the 6-bromo-2,2,5,7-tetramethylchromane in a very short time (15 min) and with a good yield (89%). Similar conditions have been applied to the synthesis of vitamin E (d,l-α-tocopherole) [38].

The application of the acidic system of ionic liquid + Brønsted acid allows one to carry out a Schmidt reaction at very mild conditions (40 °C) [34]. Synthesis of tetrazoles can be successfully carried out in acidic IL [emim][HSO₄] without the addition of sulfuric acid [39]. 5-Alkyl-2-amino-1,3.4-thiodiazole and α,ω-bis(2-amino-1,3.4-thiodiazol-5-yl)alkane have been prepared by interaction of carboxylic acids and thiosemicarbazide in [emim][HSO₄], acidified by the addition of sulfuric acid with a good to excellent yields. However, application of the [emim][HSO₄] did not allow regeneration and reuse of this catalytic system. Use of hydrophobic ionic liquid [hmim][fap] or [bmpl][fap]) instead of [emim][HSO₄] provides the possibility to regenerate and reuse the catalytic system [hmim][fap] or [bmpl][fap] + H₂SO₄ at least three times [40].

A practical approach to the synthesis of 1-(α-hydroxyalkyl)- or 1-(β-hydroxyalkyl)-2-(aminomethyl)acetylenes was developed in 2012 [41]. The authors used a catalytic system comprising a metallo-catalyst Cu(OAc)₂ in combination with acidic IL [emim][HSO₄] diluted with water to promote three components of a Mannich type reaction of terminal alcohols with formaldehyde and secondary amines. Final products were gained in better yield in comparison with those obtained in conventional organic solvents. It has been demonstrated that the catalytic system Cu(OAc)₂/[emim][HSO₄]/H₂O can be recovered and reused for several times without reducing the yield of the final product [41].

The acidic properties of N,N-dialkylimidazolium hexafluorophosphate or tetrafluoroborate ILs presumably relate to acidic proton in position two of the imidazolium ring. This can result in the in situ generation of HF due to parallel formation of a complex between nucleophilic imidazolium carbene and Lewis acids PF₅ or BF₃ according to the equilibrium presented in Scheme 1 [42].

The acidic properties of [bmim][PF₆] have been used to catalyze the Johnson–Claisen rearrangement of allylic terpenols. Natural isoprenoid-derived carboxylic esters were prepared in moderate to high yield via interaction of allylic terpenols with triethyl orthoacetate (propionate) in the presence of 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF₆] (10 mol%). This convenient protocol allows simple product separation and reuse of the ionic liquid up to ten times without reduction in the product’s yield [42].

Application of 1-butyl-3-methylimidazolium hexafluorophosphate or tetrafluoroborate ILs to promote the von Richter reaction has demonstrated the possibility to prepare some compounds which were considered to be inaccessible under known conditions described in the literature [43]. Similarly, Chapman rearrangement of aryl benzimidates to tertiary acyclic amides in [bmim][PF₆] or [bmim][BF₄] has been shown to proceed at much milder conditions (120–190 °C) than the 220–300 °C typically required for Chapman reaction [44].

The ionic nature of ILs can promote polarization of a conjugated system. For example, cations can be attached to the lone pair of the heteroatom and anion coordinate on an acidic proton promoting charge separation in the starting compound [45]. This reaction´s mechanism has been proposed to explain the unprecedented acceleration of the domino reaction between 4-hydroxyalk-3-yonates and amines in ionic liquids yielding 4-aminofuran-2(5H)-ones. Ionic liquid [bmim][BF₄] applied for this synthesis can be recycled and reused at least five times without a decrease in reaction rate and in product yield [45]. A similar acceleration effect of ionic liquid as a reaction medium has been observed by fluorocyclization (lactonization) of unsaturated carboxylic acids under action of F-TEDA-BF₄ [46].

Due to their ionic character, ionic liquids are good solvents for many organic and inorganic compounds. For instance, dehydration of N-acyl-2-arylethylamines with POCl₃ to 3,4-dihydroisoquinolines (Bishler–Napieralski reaction) has been shown to proceed in ILs such as [bmim][PF₆], [emim][CF₃SO₃], and [bmpl][CF₃SO₃] under milder conditions and with better yield in comparison to reaction in conventional solvents [47]. Similarly, high yield of benzofuroxanes has been achieved by interaction of the o-nitrobenzenes with sodium azide NaN₃ in [empl][BF₄] in the presence of phase transfer catalyst and small quantity of water [48].

However, only few examples are reported on the reaction of epoxides with thiols in ionic liquids. In some cases, addition of a catalyst was not necessary, while for some ring opening reactions of epoxides or thiols heating was required [49,50,51,52]. The most common ILs consist of dialkylimidazolium cations and [BF₄⁻], with [Br⁻] or [Cl⁻] as the counter-anion. The reactions in ILs usually provides good yields and high regioselectivity.

As a continuation of our research dealing with the study of the chemical reactivity of thiosilanes and of organoselenosilanes towards electrophiles, with the aim of the development of mild conditions to functionalize the chalcogen–Si bond, herein we report our results on the interaction of silyl sulfides and silyl selenides with epoxides, aziridines and thiiranes in RTILs. To the best of our knowledge, there is no example on the reactivity of silylated sulfur nucleophiles with these heterocycles in ionic liquids.

Previously, we have found that bis(trimethylsilyl)sulfide reacted efficiently with aldehydes in ionic liquids to afford thioaldehydes [53]. The conversion of the C=O into the C=S group required the use of a suitable catalyst as CoCl₂·6H₂O or TfOTMS. 1-R-3-Methyl imidazolium derivatives (R = Et, n-Bu, n-Hex) with [BF₄⁻], [PF₆⁻], and [TfO⁻] anions were the most efficient in promoting the thionation [53]. On the other hand, when pyrrolidinium based ionic liquids were used, only [bmpl][ntf] allowed us to obtain the expected thioaldehydes, while no reaction was observed in [bmpl][N(CN)₂]. These results confirm the influence of the cation’s and anion’s nature on the progress of this reaction. These considerations prompted us to conduct an initial and systematic survey on the reaction of thiosilanes with epoxides in ionic liquids.

2. Results

2.1. Reaction of Thio- and Selenosilanes with Epoxides

To find out the best conditions for this reaction, glycidyl isopropyl ether 1a and (phenylthio)trimethylsilane 2a were selected as model substrates for the reaction in different ionic liquids. With regard to the stoichiometric ratio between the reagents (1a and 2a), 20% excess of the silyl nucleophile was found to be the choice amount to obtain the better yield. The reaction was then performed in the most common ionic liquid [bmim][BF₄] using TBAF· xH₂O or PhONⁿBu₄ as catalyst, leading to the β-hydroxy phenylsulfide 3a in fairly good yields (

Table 1. Ring opening of glycidyl isopropyl ether by PhSTMS in [bmim][X].

Entry	Ionic Liquid	Catalyst	Time	Yield (%) a
				3a	4a
1	[bmim][BF4]	TBAF·xH2O (20%)	2 h	58 b	-
2	[bmim][BF4]	PhONnBu4 (40%)	4 h	51 b	-
3	[bmim][BF4]	-	12 h	10 c	13
4	[bmim][BF4]	-	48 h	24 d,e,f	27
5	[bmim][PF6]	TBAF·xH2O (20%)	3 h	47 b,e	-
6	[bmim][PF6]	-	3 h	28 c,e,f	22

^a Isolated yield. ^b Traces of diphenyl disulfide were isolated. ^c 24% of (PhS)₂. ^d 33% of (PhS)₂. ^e Unreacted epoxide (ca. 25–30%) was recoverd. ^f ca. 40% after desilylation with TBAF (10%).

, entries 1, 2). In the absence of any catalyst, a mixture of sulfides bearing in β-position the hydroxyl (3a) or the silylether (4a) moiety were isolated in low yield (Table 1, entries 3, 4). Formation of hydroxy-derivate (3a) is presumably related to the presence of acidic impurities in the [bmim][BF₄] applied for this synthesis. This result indicates that ionic liquid [bmim][BF₄] is able to promote the ring opening, though longer reaction time (12–48 h) is required in this case. A similar result was achieved when the epoxide 1a was reacted in [bmim][PF₆] (Table 1, entries 5, 6), giving 3a in 47% yield when TBAF·xH₂O was employed as catalyst. However, in the absence of the catalyst, 3a and 4a were isolated in low yield (entry 6), though in shorter reaction time of 3 h in comparison with the reaction in [bmim][BF₄]. Presumably, in situ hydrolysis of the [bmim][PF₆] by traces of water or equilibrium, depicted in Scheme 1 (see above), leads to generation of the HF, which act as catalyst and proton source in this reaction. Complete desilylation of a mixture of sulfides (3a) and (4a) was achieved by treating this mixture with TBAF·xH₂O (10%). In all cases, the ring opening occurred with high regioselectivity, allowing isolation of the product deriving from the nucleophilic attack on the less substituted position of the epoxide.

The ring opening reaction was extended to various substituted epoxides, such as benzyl glycidyl ether 1b (S-isomer), (±)-propylene oxide 1c, and (±)-styrene oxide 1d, affording the desired products 3b–d in good yields in the presence of TBAF·xH₂O (

Table 2. Ring opening of epoxides by PhSTMS in [bmim][BF₄].

Entry	R	Catalyst	Time	Product	Yield (%) a,b
1	CH2OiPr (±)-1a	TBAF·xH2O (20%)	3 h		58
2	CH2OBn (S)-(+)-1b	TBAF·xH2O (20%)	3 h		63
3	CH2OBn (S)-(+)-1b	-	26 h		44
4	CH3 (±)-1c	TBAF·xH2O (20%)	2 h		39
5	CH3 (±)-1c	-	26 h		14
6	C6H5 (±)-1d	TBAF·xH2O (20%)	3.5 h		61 (3d) 11 (5)

^a Isolated yield. ^b 20–25% of disulfide (PhS)₂ was formed. ^c Desilylation with TBAF (10%) was accomplished. ^d Ratio determined by ¹H-NMR.

, entries 2, 4, 6). Meanwhile, without catalysis, the yields were much less and longer reaction times were required to complete the reaction (Table 2, entries 3, 5). When epoxide 1d was used as substrate, a mixture of regioisomers 3d and 5 was obtained (3d:5 = 6:1, Table 2, entry 6), similarly to that which was observed in the organic solvents [17,54].

However, these preliminary results indicate that the reaction of organothiosilanes with epoxides can proceed efficiently also in [bmim][BF₄] as reaction media. Taking into account that the nature of anions and cations has an impact on the properties of ionic liquids, we were interested to test diverse ionic liquids, such as 1-alkyl-3-methyl imidazolium derivatives, bearing alkyl chains of different length, and methyl pyrrolidinium salts in ring opening reactions.

Thus, reaction of the epoxide 1a with PhSTMS in various ionic liquids in absence of catalysts is summarized in

Table 3. Thiolysis of glycidyl isopropyl ether by PhSTMS in different ILs.

Entry	Ionic Liquid	Catalyst/T(°C)	Time	3a:4a	Yield (%) a,b
1	[emim][msu]	-/rt	2 h	1:1.2 c	73
2	[emim]atf]	-/rt	2 h	1:1.6 c	78
3	[bmpl][dca]	-/rt	2 h	1:1.6 c	78
4	[emim][otf]	-/rt	4 h	> 1:9 c	16
5	[emim][otf]	TBAF·xH2O d/rt	2 h	> 9:1	28
6	[hmim][ntf]	-/rt	3 h	> 1:9 c	27
7	[hmim][ntf]	TBAF·xH2O d/rt	2 h	> 9:1	66
8	[hmim][ntf]	-/70 °C	6 h	1:1.4 c	65
9	[hmim][fap]	TBAF·xH2O d/rt	2 h	> 9:1	52
10	[bmpl][ntf]	TBAF·xH2O d/rt	1.5 h	> 9:1	58
11	[bmpl][ntf]	-/70 °C	3 h	1:1.7 c	63
12	[bmpl][fap]	TBAF·xH2O d/rt	2 h	> 9:1	26
13	[bmpl][fap]	-/70 °C	6 h	1:1.1	37

^a Total yield. ^b 15–20% of diphenyl disulfide was formed. ^c Desilylation was carried out with 10% TBAF. ^d 20% of TBAF was added.

. The desired hydroxyl sulfide 3a was regioselectively obtained in good yield, alongside the corresponding silyl ether 4a, in hygroscopic ILs [emim][msu], [emim][atf], and in [bmpl][dca] (Table 3, entries 1–3). The ring opening proceeded less efficiently in [emim][otf] as reaction media (Table 3, entries 4, 5). It is interesting to note that in the absence of catalyst the ratio 3a:4a is of about 1:9 (total yield is 16%, entry 4), and is reversed to about 9:1 (total yield is 28%, entry 5) when TBAF·xH₂O is used as catalyst. Addition of TBAF·xH₂O or heating (70 °C) were necessary to obtain the ring opening products in hydrophobic ILs [hmim][ntf] and [bmpl][ntf] as reaction media (Table 3, entries 6–8, 10, 11). A similar result was obtained in the reaction of 1a with 2a in [hmim][fap] and [bmpl][fap] (Table 3, entries 9, 12, 13). This could be ascribed to the hydrolytic stability and the low coordination ability of the [ntf] and [fap] anions in these ionic liquids.

A plausible explanation of the uncatalyzed reactions in the dialkyl imidazolium series could stem from the possible activation of the epoxide by the imidazolium ring, due to a certain acidity of the H2 hydrogen (pK_a = 21–23) [25], or by presence of traces HF in case of [BF₄] and [PF₆] ionic liquids.

However, the anion can play an important role: [emim] methylsulfate and trifluoroacetate were able to catalyze the nucleophilic ring opening reaction (NROR) better than [emim] trifluoromethylsulfonate (otf), which is a weak nucleophile. [25] Considering the pyrrolidinium series, only [bmpl][dca] behaved as an efficient catalyst (Table 3, entry 3). It seems that nucleophilic dicyanamide (NC)₂N⁻ [dca]-anion of this ionic liquid is able to efficiently functionalize the S–Si bond, enabling the nucleophilic attack on the epoxide. Nonetheless, in case of ionic liquids with weakly coordinating anions [bmpl][ntf] or [bmpl][fap], catalysis with TBAF·xH₂O or heating were required to obtain the products 3a and 4a_. However, the yield was rather low, which confirms the influence of the anion’s nucleophily on the progress of ring opening reaction (Table 3, entries 10–13).

The work up after completion of the reaction was simple. The products were extracted with diethyl ether, except for reactions carried out in [hmim][ntf] and [hmim][fap], where hexane was employed, and [bmpl][fap] which required extraction with chloroform, since these ionic liquids are miscible or partially miscible with Et₂O.

In order to enlarge the scope of this protocol, the uncatalyzed reaction was extended to other monosubstituted epoxides (

Table 4. Ring opening reactions of mono- and disubstituted epoxides 1b,d–f.

Entry	R	R1	Ionic Liquid	Conditions	Products	Yield (%) a,b
1	CH2OBn (R)-(-)-1b	H	[emim][msu]	r.t./2 h	3b:4b > 10:90	65 (59) c,d
2	C6H5 (±)-1d	H	[emim][atf]	r.t./3.5 h	(3d,4d):(5,6) > 30:70 e	59 (58) f
3	C6H5 (±)-1d	H	[bmpl][dca]	r.t./3.5 h	(3d,4d):(5,6) > 20:80 e	67 (65) f
4	CH2OH (S)-(-)-1e	H	[emim][atf]	r.t./2.5 h	3e:4e > 10:90	60 (57) c
5	1f		[emim][msu]	TBAF·xH2O 70 °C/18 h	3f	38 c,g
6	1f		[emim][atf]	TBAF·xH2O 18 h	3f	27 c,h
7	1f		[bmpl][dca]	TBAF·xH2O 70 °C/18 h	3f	<10 c,i

^a Total isolated yield. ^b In parenthesis yield of 3 after desilylation (TBAF 10%). ^c ca. 15–20% of (PhS)₂. ^d Unreacted epoxide (ca. 15%) was recovered.^e,f Ratio of regioisomers (3d,4d):(5,6) = 3:1 and total yields determined by ¹H NMR. ^g ca. 30% of unreacted epoxide. ^h ca. 50% of unreacted epoxide.ⁱ ca. 70% of epoxide.

, entries 1–4), showing that the selected ionic liquids with nucleophilic counter anions [msu], [atf], and [dca] were able to perform as reaction medium and as catalysts, enabling formation of the β-substituted phenyl sulfides in good yields.

A high regioselectivity was achieved, except for the styrene oxide which, as already observed [17,54], gave a mixture of regioisomeric β-hydroxy-(5) and β-trimethylsilyloxy- (6) substituted sulfides (Table 4, entries 2, 3). Reaction of chiral non-racemic (R)-(-)-benzyl glycidol 1b and (S)-(-)-glycidol 1e with the thiosilane allowed access to chiral β-hydroxy- or β-OTMS-phenylsulfides (3b,e or 4b,e, respectively) with retention of stereoselectivity. When the disubstituted epoxide 1f of d-mannitol was used as substrate, addition of the TBAF or heating and a longer reaction time were required in all the ILs used. In spite of the more hard conditions, a low conversion rate for 1f was observed (Table 4, entries 5–7). These results indicate the low reactivity of this disubstituted substrate.

To expand the application of ionic liquids as reaction media in epoxide ring-opening reaction, we tested a more intriguing thiosilane, the bis(trimethylsilyl)sulfide 2b (hexamethyldisilathiane, HMDST). The interaction of 1a with HMDST was carried out in selected ionic liquids, as summarized in

Table 5. Thiolysis of glycidyl isopropyl ether by HMDST in selected ILs.

Entry	Ionic Liquid	Catalyst	Time	Products	Yield (%) a
1	[bmim][BF4]	-	24 h	12	8 b
2	[bmim][BF4]	TBAF·xH2O (20%)	2 h	7:9:11 = 1:1:1 c	40 c
3	[emim]msu]	-	5 h	12:11 > 95:5	28
4	[emim]msu]	TBAF·xH2O (20%)	2 h	9:11 = 1:3 c	36 c
5	[emim][atf]	-	4 h	12:9 > 95:5	35
6	[emim][atf]	TBAF·xH2O (20%)	90 min	9:11 > 95:5	33 d
7	[emim][atf]]	TBAF·xH2O (20%)	30 min	7:(9 + 11) > 95:5	56
8	[bmpl][dca]	-	5 h	12:11 > 95:5	27
9	[bmpl][dca]	TBAF·xH2O (20%)	3 h	9:11 = 1:2 c	35 c

^a Total yield. ^b Unreacted epoxide (ca. 63%) was recoverd.^c Yields and products ratio determined by ¹H NMR. ^d Epoxide:HMDST 2:1.

. In the absence of catalysis, the ring opening reaction in [bmim][BF₄] resulted in poor conversion and formation of a small quantity of the β-trimethylsilyloxy disulfide 12 (Table 5, entry 1). Conversely, when TBAF was added as catalyst, an almost equimolar mixture of β-mercapto alcohol 7, β-hydroxy disulfide 11 and β-hydroxy sulfide 9 was obtained within 2 h of reaction time (Table 5, entry 2).

On the other hand, the thiolysis of 1a was achieved without TBAF in [emim][msu], [emim][atf] and [bmpl][dca], leading to the disulfide 12 as the major product, however the yields were low (Table 5, entries 3, 5, 8). The formation of the disulfide or sulfide could be ascribed to the rather long reaction time (4–5 h) required to reach a good conversion. That could favor the oxidation of the thiol intermediate to disulfides 11 and 12, or otherwise its further attack on the epoxide to form the sulfide 9, as was observed when an excess of epoxide was reacted under TBAF catalysis (Table 5, entry 6). Application of the TBAF as catalyst allowed us to achieve better selectivity by shorter reaction time and to increase the yield. When the catalyst was used in [emim][msu] and [bmpl][dca], a mixture of products 9 and 11 was obtained (Table 5, entries 4, 9), while the thiol 7 was found to be a major compound by interaction of 1a with HMDST 2b after 30 min in [emim][atf] (Table 5, entry 7). Based on these results, we can conclude that thiolysis of epoxides by thiosilanes in ionic liquids occurs under milder conditions in comparison with the reaction with thiols, which need a higher temperature (50–100 °C) [49,50].

The functionalization of oxiranes with silyl chalcogenides was extended to selenosilanes, providing access to seleno-derivatives, which are applicable in different fields such as organic synthesis [55,56,57], materials [58], medicinal and food chemistry [59,60,61,62,63]. Reaction of the epoxide 1a with (phenylseleno)trimethylsilane 13 in selected ionic liquids resulted in the formation of the β-hydroxy-(14a), or β-silyloxy-phenylselenide (15a) in good yields (

Table 6. Ring opening of epoxides by PhSeTMS in selected ILs.

Entry	R	R1	Ionic Liquid	Conditions	14:15	Yield (%) a
1	CH2OiPr 1a	H	[emim][msu]	r.t./90 min	1:1	72 b,c
2	CH2OiPr 1a	H	[hmim][ntf]	r.t./90 min	2:1	70 b,c
3	CH2OiPr 1a	H	[hmim][fap]	r.t./90 min	2:1	58 b,c
4	CH2OiPr 1a	H	[bmpl][ NTf2]	r.t./90 min	2:1	64 b,c
5	CH2OiPr 1a	H	[bmim][PF6]	r.t./90 min	1.5:1	72 b,c
6	1f		[emim][msu]	TBAF·xH2O r.t./18 h	>99:1	16 d,e
7	1f		[emim][atf]	TBAF·xH2O r.t./18 h	>99:1	12 d,e
8	1f		[bmpl][dca]	70 °C/18 h	>99:1	<10 e

^a Total yield. ^b 25–30% of diphenyl diselenide was obtained. ^c Desilylation with TBAF (10%) led to 14a in quantitative yields.^d 60% of TBAF was added portionwise. ^e ca. 55% of unreacted epoxide and 20% of (PhSe)2 were detected.

, entries 1–5). Addition of the catalyst to reaction mixture was not required to complete the reaction in a short time. It seems that all ionic liquids used in this reaction act as efficient catalysts, enabling nucleophilic addition of the selenosilane to epoxide. The Se–Si compounds, as expected, are more reactive than the substances containing S–Si bond. In fact, the nucleophilic ring opening with seleno-derivatives was achieved without catalysis in ILs with a weakly nucleophilic anion, i.e., in [hmim][ntf] and [bmpl][ntf], while completing the reaction with corresponding thiosilane 2a required heating or the addition of TBAF (Table 3).

The disubstituted epoxide 1f was also tested in the reaction with PhSeTMS in ionic liquids used for the interaction with PhSTMS. However, no reaction was evidenced without addition of a catalysis. After addition of TBAF, the disubstituted β-hydroxy phenylselenide 14f was isolated from the reaction mixture, albeit in very low yields (Table 6, entries 6, 7). Presence of a significant amount of unreacted epoxide was detected in this case. No increase in yield was observed after heating in [emim][msu] and [emim][atf], while in [bmpl][dca] the formation of a small quantity of product 14f was observed after prolonged heating (Table 6, entry 8). These results indicate that, despite the higher reactivity expected for silyl selenides, the disubstituted epoxide shows very poor reactivity towards these reagents.

2.2. Reaction of Thio- and Selenosilanes with Aziridines

Aiming to evaluate the scope and limitations of the proposed protocol, the reaction of thiosilanes was extended to aziridines. Aziridines represent a versatile class of compounds, being employed as useful building blocks in organic synthesis and to prepare more complex molecules with various biological properties, as well as for a variety of applications in organic chemistry [64]. In this context, the nucleophilic ring opening in aziridines is a well-established method to prepare nitrogen containing bifunctional intermediates. The reactivity of aziridines is influenced by substituent on the nitrogen: electron withdrawing groups, such as sulfonyl or carbonyl, tend to favor the ring opening when compared with aziridines, bearing N–H, N-Alk or N-Aryl groups. Only a few examples of the reaction of aziridines with chalcogen nucleophiles in ionic liquids are reported in the literature. For example, interaction of N–H aziridines with thiols proceeded efficiently in [bmim][X] (X = Cl, Br) in the absence of any catalyst [65]. β-Seleno amines can be prepared by heating aziridines with diselenides in the presence of CuO nanoparticles [66] or by use of stable zinc selenolate (PhSeZnBr) [67]. However, to the best of our knowledge, no examples dealing with the application of silyl-chalcogenides in reaction with aziridines are reported in the literature.

First, we tested the reactivity of the N-tosyl aziridine 16, prepared from l-valine, towards PhSTMS 2a in [bmim][BF₄] and [bmim][PF₆]. Despite the activation by the Ts-group, no ring opening was observed without catalysis, while in the presence of TBAF·xH₂O (20%) a regioselective formation of the chiral β-thio N-Ts-amine 17 was achieved (Scheme 2). Reaction of the silyl-selenide 13 with aziridine 16 under TBAF catalysis led to the formation of the β-seleno amine 18, together with diphenyl diselenide (ca. 30%) (Scheme 2).

In the next step we focused on testing the reactivity of N-Boc aziridines; considering that Boc deprotection is generally more practical than removal of the tosyl group. Preliminary investigations showed that the reaction of N-Boc aziridines with silyl chalcogenides (PhChSiMe₃) in THF under TBAF catalysis yielded expected β-phenylchalcogenated derivatives [68]. Use of HMDST 2b and HMDSS in this reaction led to the formation of the N-Boc amino thiols and the mixture of amino selenides and diselenides, respectively [19,69].

Like the interaction of the N-tosyl aziridine 16 (Scheme 2), the reaction of the N-Boc aziridine 19a, obtained from methionine, with PhSTMS in the absence of catalyst in [bmim][PF₆] resulted in the formation only of a small quantity (13%) of ring opening product. Mainly unreacted aziridine was recovered (65%). Addition of TBAF·xH₂O (20%) to the reaction mixture enabled the formation of 20a in 48% yield, together with diphenyl disulfide (30%) (

Table 7. Reaction of PhChSiMe₃ with N-Boc aziridines 19a,b.

Entry	R	Ch	Ionic Liquid	Conditions	Product	Yield (%) a
1	(CH2)2SMe	S	[bmim][PF6]	TBAF·xH2O/r.t./6 h	20a	48 b
2	(CH2)2SMe	S	[emim][atf]	r.t./3 h	20ac	57
3	(CH2)2SMe	S	[bmpl][dca]	r.t./3 h	20a	54
4	(CH2)2SMe	S	[emim][otf]	TBAF·xH2O/r.t./2 h	20a	63
5	(CH2)2SMe	S	[hmim][fap]	TBAF·xH2O/r.t./2 h	20a	56
6	(CH2)2SMe	S	[emim][msu]	TBAF·xH2O/r.t./3 h	20a	61
7	(CH2)2SMe	S	[hmim][ntf]	TBAF·xH2O/r.t./3 h	20a	49
8	(CH2)2SMe	S	[bmpl][ntf]	TBAF·xH2O/r.t./3 h	20a	65
9	(CH2)2SMe	S	[bmpl][fap]	TBAF·xH2O/r.t./3 h	20a	43
10	(CH2)2SMe	Se	[bmim][PF6]	TBAF·xH2O/r.t./4 h	21ac,d	45
11	(CH2)2SMe	Se	[emim][msu]	r.t./3 h	21a	54
12	(CH2)2SMe	Se	[hmim][fap]	r.t./3 h	21a	42
13	(CH2)2SMe	Se	[bmpl][ntf]	r.t./3 h	21a	68
14	i-Pr	S	[bmim][PF6]	TBAF·xH2O/r.t./4 h	20b	48
15	i-Pr	S	[emim][atf]	r.t./3 h	20bc,d	55
16	i-Pr	S	[bmpl][dca]	r.t./6 h	20b	59 e
17	i-Pr	S	[hmim][ntf]	70°C/10 h	20b	47
18	i-Pr	S	[bmpl][ntf]	TBAF·xH2O/r.t./3 h	20b	38 f
19	i-Pr	S	[hmim][fap]	TBAF·xH2O/r.t./2 h	20b	46
20	i-Pr	Se	[bmim][PF6]	TBAF·xH2O/r.t./3 h	21b	47

^a Isolated product. ^b Without catalysis 65% of unreacted aziridine was recovered. ^c Minor regioisomer PhChCH(R)CH₂NHBoc (10%) was observed. ^d 20% of the minor regioisomer. ^e 10% of unreacted aziridine. ^f 45% of unreacted aziridine.

, entry 1). Application of [emim][atf] and [bmpl][dca] as reaction media allowed us to obtain 20a in satisfactory yield without the use of any catalyst (Table 7, entries 2, 3). Formation of the β-amino phenylsulfide 20a in other ionic liquids with less nucleophilic anions was achieved only after addition of TBAF·xH₂O (20%) to the reaction mixture (Table 7, entries 4–9).

Similarly, PhSeTMS 13 reacted with aziridine 19a in [bmim][PF₆] under TBAF catalysis yielding 21a (Table 7, entry 10). Interestingly, when other ionic liquids were used (Table 7, entries 11–13), no addition of catalyst was necessary to isolate the ring-opening product 21a.

The reaction’s conditions described above were also applied to the TBAF catalyzed interaction of aziridine 19b, derived from valine, with PhSTMS 2a and PhSeTMS 13 (Table 7, entries 14, 20) in [bmim][PF₆], as well as in other ionic liquids (Table 7, entries 18, 19). In all cases the yields of N-Boc amino thiol 20b and amino selenide 21b were moderate (38–47%). Heating of reactants in [hmim][ntf] led to the formation of the amino thiol 20b in 47% yield (Table 7, entry 17). Application of the catalyst TBAF is not required in this case. Similarly, reaction of the of aziridine 19b with PhSTMS 2a in [emim][atf] and [bmpl][dca] can be carried out without application of the catalyst (Table 7, entries 15, 16). This observation confirms that ionic liquid with nucleophilic anions can induce the nucleophilic substitution by 2a in the absence of any catalyst. The results presented in Table 7 highlight how ionic liquids are suitable reaction media to promote the ring opening reaction of less activated aziridines by silyl-chalcogenides under mild conditions. Furthermore, these reactions proceeded under high regiocontrol, enabling the isolation of the products arising from the attack on the less hindered side of aziridine. Only when reactions of the aziridines 19a and 19b with PhSTMS 2a were carried out in [emim][atf] (Table 7, entries 2, 15) were the regioisomers (PhSCH(R)CH₂NHBoc, R = (CH₂)₂SMe, i-Pr) derived from the attack on the more substituted side of the aziridine detected in the reaction mixture as minor products. Moreover, the formation of a minor regioisomer was observed in the reaction between aziridine 19a with the selenated nucleophile PhSeTMS 13 in [bmim][PF₆] (Table 7, entry 10).

The reaction of aziridine 19a with bis(trimethylsilyl)sulfide HMDST 2b did not proceed without catalyst in selected ionic liquids. In fact, after 8–10 h, unreacted aziridine was recovered. Addition of TBAF to the reaction mixture initiated the ring opening reaction leading to the formation of the β-amino disulfide 22 as major product, together with the amino thiol 23 in somewhat lower yields (

Table 8. Ring opening of N-Boc aziridine 19a by HMDST in selected ILs.

Ionic Liquid	Time	Products	Yield (%) a
[bmim][PF6]	5 h	22	28
[emim][atf]	3 h	22:23 = 4:1	48 b,c
[bmpl][dca]	1.5 h	22:23 = 4:1	52 b,c
[emim][msu]	3 h	22:23 = 3:1	61 b,c

^a Isolated yield. ^b Total yield of 22 and 23 (not separated). ^c Ratio determined by NMR.

).

2.3. Reaction of Thio- and Selenosilanes with Thiiranes

Among strained heterocycles, thiiranes also represent interesting building blocks and intermediates in different organic transformations to prepare a variety of molecules, including sulfurated heterocycles, through ring expansion routes [70]. Nevertheless, thiiranes have received less attention, probably due to their lower stability in comparison to other three-membered derivatives discussed above. In fact, in the presence of strong nucleophiles they are subjected to desulfurization to the corresponding alkenes, while the reaction with weak nucleophiles leads to polymerization resulting in polysulfides [71]. Moreover, the nucleophilic ring opening gives thiols, whose high tendency to oxidation to disulfides is well known. Thiols are identified to play an important role in some biochemical transformations due to their capability to be oxidized and then regenerated, such as in sugar derivatives [72], and to be noteworthy intermediates for the development of novel spice compounds and aromas [73]. Therefore, a mild and straightforward method for the ring opening of thiiranes to prepare the corresponding thiol-containing derivatives is highly desirable. Several methods dealing with the reaction of thiiranes with thiols or thiolates to obtain mercapto sulfides through a S_N2 ring opening reaction in the presence of suitable catalysts have been reported. It has been observed that the product’s distribution pattern depends on the reaction conditions, such as the type of the nucleophile, the solvent polarity, the concentration, and the reaction temperature [74,75].

It was decided that we should investigate the reaction of thiiranes with thiosilanes in ionic liquids. To the best of our knowledge, no ring opening of thiiranes with any nucleophile in these reaction media have been reported. At first, the interaction of the 2-(isopropoxymethyl)thiirane 24 with thiosilane 2a was carried out in [bmim][PF₆], but no reaction was observed. After addition of TBAF·xH₂O (20%) to the reaction mixture and stirring for 6 h the major isolated compound was the disulfide 26 (

Table 9. Reaction of thioglycidyl isopropyl ether 24a with PhSSiMe₃ and PhSeSiMe₃.

Entry	Ionic Liquid	Conditions	Products	Yield (%) a,b
1	[bmim][PF6]	TBAF·xH2O/r.t./6 h	26	52
2	[emim][msu]	r.t./2 h 30 min	25, 26	56 c,d
3	[emim][atf]	TBAF·xH2O/r.t./4 h	25, 26	54 c,d
4	[hmim][ntf]	r.t./3 h	25, 26	59 c,d
5	[bmpl][ntf]	r.t./2 h 30 min	25, 26	48 c,d
6	[hmim][fap]	r.t./2 h 30 min	25, 26	45 d,e
7	[bmpl][fap]	TBAF·xH2O/r.t./4 h	25, 26	49 d,f,g
8	[bmpl][dcn]	r.t./2 h	27	30 f
9	[emim][otf]	TBAF·xH2O/r.t./2 h	25, 26, 27	57 f,h,i
10	[hmim][fap]	TBAF·xH2O/r.t./3 h	28, 29	42 l.m

^a Isolated product. ^b 10–15% of (PhS)₂ was formed (except entry 10). ^c Total yield of 25 and 26 (not separated; ca. 1:4 by NMR). ^d 10–15% of 27 was detected (GC/MS and NMR). ^e Total yield of 25 and 26 (ca. 1:6 by NMR). ^f Polysulfides were detected by mass spectra. ^g Comparable result was achieved at 50 °C/5 h. ^h Total yield (by NMR). ⁱ 25:(26 + 27) = 1:2 (by NMR). ^l Total yield of 28:29 (not separated; ca. 1:8 by NMR). ^m 5% of (PhSe)₂ was formed.

, entry 1). The disulfide 26 was generally the major compound obtained in all reactions listed in the Table 9 together with a small quantity of the β-phenylthio thiol 25, except the reaction in [bmpl][dcn], in which the mixed sulfide 27 was isolated in low yield as the only product. The reaction carried out in [emim][atf], [bmpl][fap] and [emim][otf] required the addition of TBAF to achieve the thiirane ring opening (Table 9, entries 3, 7, 9). In [bmpl][fap] a similar result was obtained when the reaction mixture was heated at 50 °C for 4 h (Table 9, entry 7, footnote ‘g’). Mixed sulfide 27 was identified by GC–MS, even if in rather low amount, in the reaction mixture obtained in [emim][otf] (Table 9, entry 9). Presumably, compound 27 resulted from nucleophilic attack of the thiol moiety of 25 on a second molecule of the thiirane. It can be observed, the uncatalyzed ring opening was obtained in several ionic liquids (Table 9, entries 2, 4–6, 8), leading to a similar distribution of products.

Fluoride induced ring opening of episulfide was also observed with the Se-nucleophile 13. The β-phenylseleno disulfide 29 was formed as major product in this reaction together with small quantity of the β-mercaptoselenide 28 (Table 9, entry 10).

3. Materials and Methods

3.1. Instruments and Reagents

All reactions were carried out in an oven-dried glassware under inert atmosphere (N₂). All commercial products were purchased from Merck-Sigma-Aldrich and used as received, without further purification. The ionic liquids used were prepared ([bmim][BF₄], [bmim][PF₆]) according to reported methods, or gently provided by Merck ([emim][otf], [emim][msu], [emim][atf], [hmim][fap], [hmim][ntf], [[bmpl][ntf], [bmpl][dcn], [bmpl][fap]). Abbreviations used for ionic liquids are reported in

Table 10. Abbreviations of ionic liquids.

Abbreviations of Ionic Liquids	Full Name	Anions	Cations
[bmim][BF4]	1-Butyl-3-methylimidazolium tetrafluoroborate	[BF4−]
[bmim][PF6]	1-Butyl-3-methylimidazolium hexafluorophosphate	[PF6−]
[emim][otf]	1-Ethyl-3-methylimidazolium trifluoromethanesulfonate	[CF3SO3−]
[emim][msu]	1-Ethyl-3-methylimidazolium methylsulfate	[CH3OSO3−]
[emim][atf]	1-Ethyl-3-methylimidazolium trifluoroacetate	[CF3COO−]	(Alk = n-Butyl, Ethyl, n-Hexyl)
[hmim][fap]	1-Hexyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate	[(C2F5)3PF3−]
[hmim][ntf]	1-Hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide	[N(CF3SO2)2−]
[bmpl][ntf]	1-Butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide	[N(CF3SO2)2−]
[bmpl][dcn]	1-Butyl-1-methylpyrrolidinium dicyanamide	[N(CN)2−]
[bmpl][fap]	1-Butyl-1-methylpyrrolidinium tris(pentafluoroethyl)trifluorophosphate	[(C2F5)3PF3−]

. Ionic liquids were maintained under high vacuum for 30 min prior to use. Thin layer chromatography was performed with TLC plates silica gel 60 F₂₅₄, which was visualized under UV light, or by staining with an ethanolic acid solution of p-anisaldehyde followed by heating. Mass spectra were determined by ionization potential (EI, 70 eV) and by ESI. NMR spectra (¹H and ¹³C) were recorded in CDCl₃ using Varian Gemini 200 or a Mercury 400 operating at 200 or 400 MHz for ¹H and 50 or 100 MHz for ¹³C. ⁷⁷Se NMR spectra were recorded using a Bruker 400 Ultrashield spectrometer, operating at 76 MHz. NMR signals were referenced to nondeuterated residual solvent signals (7.26 ppm for ¹H, 77.0 ppm for ¹³C). Diphenyl diselenide (PhSe)₂ was used as an external reference for ⁷⁷Se NMR (δ = 461 ppm). Chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given in Hertz (Hz), rounded to the nearest 0.1 Hz. Multiplicity is reported as s = singlet, d = doublet, t = triplet, ap d = apparent doublet, m = multiplet, dd = doublet of doublet, bs = broad singlet, and bd = broad doublet. Line separation = ls.

3.2. Experimental Method

3.2.1. General Procedure for the Ring Opening of Epoxides 1 by (phenylthio)trimethylsilane 2a and (phenylseleno)trimethylsilane 13

A mixture of epoxide (1 eq., 100–150 mg) and silyl nucleophile (PhSTMS 2a or PhSeTMS 13) (1.2 eq.) in the ionic liquid (0.5 mL) was stirred at room temperature. The progress of the reaction was followed by TLC (typically: hexanes/ethyl acetate 9:1) upon extraction with diethyl ether of a small amount of the reaction mixture. After completion, the reaction mixture was extracted with diethyl ether (3 × 2 mL) or hexanes (depending on the miscibility of the ionic liquid with the organic solvent). The combined organic extracts were dried over Na₂SO₄ and then concentrated under vacuum to obtain the crude product. The ionic liquid can be reused after drying under vacuum to eliminate traces of the extraction solvent.

When required, following the previously described procedure, TBAF·xH₂O (20%) was added to the reaction mixture of the epoxide (1 eq.) and the silyl nucleophile (1.2 eq.) in 0.5 mL of the ionic liquid. When the reaction was performed without catalyst, a mixture of alcohol (3 or 14) and silyl ether (4 or 15) was obtained. Treatment of the crude product with 10% TBAF (1M in THF) afforded the deprotected β-hydroxy-phenyl sulfide 3 or selenide 14. The crude products can be purified on silica gel (petroleum ether:ethyl acetate=6:1 or 4:1).

1-Isopropoxy-3-(phenylthio)propan-2-ol, 3a

Yellowish oil, yield: see Table 1, Table 2, Table 3 and Table 4. ¹H NMR (200 MHz, CDCl₃), δ (ppm): 1.15 (d, 6H, J = 6.2 Hz); 2.43 (br s, 1H, OH), 3.05–3.11 (m, 2H), 3.40–3.63 (m, 2H + 1H), 3.81–3.92 (m, 1H), 7.18–7.41 (m, 5H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 22.1, 37.6, 69.2, 70.3, 72.3, 126.2, 128.9, 129.5, 135.1. MS, m/z (%): 226 (M⁺, 58), 135 (63), 123 (69), 109 (68), 99 (100).

[(1-Isopropoxy-3-(phenylthio)propan-2-yl)oxy]trimethylsilane, 4a

Yellow oil, yield: see Table 1, Table 2 and Table 3. ¹H NMR (200 MHz, CDCl₃), δ (ppm): 0.11 (s, 9H), 1.15 (d, 6H, J = 6Hz), 2.98 (dd, 1H_A, J = 6.6 Hz, 13.6 Hz), 3.19 (dd, 1H_B, J = 4.8 Hz, 13.6 Hz), 3.45 (app dd, 2H, J = 4.6 Hz, 5.3 Hz), 3.49–3.64 (m, 1H), 3.94 (app quint, 1H, J = 5.2 Hz), 7.38–7.42 (m, 5H). MS, m/z (%): 298 (M⁺, 10), 225 (17), 135 (82), 117 (65), 99 (76), 73 (100). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 0.46, 22.1, 37.6, 69.2, 70.3, 72.3, 126.2, 128.9, 129.5, 135.1. MS, m/z (%): 298 (M⁺, 10), 225 (18), 135 (82), 117 (64), 99 (61), 73 (100).

(R)-1-(benzyloxy)-3-(phenylthio)propan-2-ol, 3b

Light yellow oil, yield: see Table 2 and Table 4. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 2.61 (br d, 1H, J = 4.5 Hz), 3.02 (dd, 1H_A, J = 7.3 Hz, 14.1 Hz), 3.14 (dd, 1H_B, J = 4.9 Hz, 14.1 Hz), 3.50 (dd, 1H_A, J = 5.7 Hz, 10.0 Hz), 3.59 (1H_B dd, J = 4.3 Hz, 10.0 Hz), 3.84–3.96 (m, 1H), 4.53 (br s, 2H), 7.18–7.38 (m, 10H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 37.5, 68.9, 72.3, 73.4, 127.4, 127.7, 128.2, 128.5, 128.9, 129.6, 135.3, 137.7. MS, m/z (%): 274 (M⁺, 4), 135 (19), 123 (22), 109 (16), 91 (100).

[(1-(Benzyloxy)-3-(phenylthio)propan-2-yl)oxy]trimethylsilane, 4b

Yellow oil, yield: see Table 2 and Table 4. ¹H NMR (200 MHz, CDCl₃), δ (ppm): 0.09 (s, 9H), 2.99 (dd, 1H_A, J = 6.7 Hz, 13.5 Hz), 3.21 (dd, 1H_B, J = 5.6 Hz, 13.5 Hz), 3.49–3.59 (m, 2H), 3.90–4.06 (m, 1H), 4.52 (br s, 2H), 7.20–7.40 (m, 10H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 0.44, 37.7, 71.0, 72.9, 73.2, 126.0, 127.6, 128.6, 128.9, 129.5, 136.7. MS, m/z (%): 346 (M⁺, 3), 135 (44), 91 (100), 73 (68).

1-(Phenylthio)propan-2-ol, 3c

Light yellow oil, yield: see Table 2. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.27 (d, 3H, J = 6.2 Hz), 1.88 (br s, 1H), 2.84 (dd, 1H_A, J = 8.8 Hz, 13.6 Hz), 3.13 (dd, 1H_B, J = 3.9 Hz, 13.6 Hz), 3.79–3.87 (m, 1H), 7.16–7.41 (m, 5H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 22.0, 43.7, 65.6, 127.4, 128.9, 130.1, 135.0. MS, m/z (%): 168 (M⁺, 29), 124 (63), 109 (20), 91 (39), 45 (100).

Trimethyl[(1-(phenylthio)propan-2-yl)oxy]silane, 4c

Yellow oily liquid, yield: see Table 2. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 0.09 (s, 9H), 1.26 (d, 3H, J = 6.0 Hz), 2.89 (dd, 1H_A, J = 6.3 Hz, 13.1 Hz), 3.06 (dd, 1H_B, J = 5.9 Hz, 13.1 Hz), 3.94 (br sext, 1H, J = 6.2 Hz), 7.12–7.40 (m, 5H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 0.39, 24.2, 44.3, 68.5, 125.9, 128.2, 129.1, 134.5. MS, m/z (%): 240 (M⁺, 12), 117 (91), 73 (100).

1-Phenyl-2-(phenylthio)ethan-1-ol, 3d

Yellow oil, yield: see Table 2 and Table 4. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 2.81 (br s, 1H), 3.09 (dd, 1H_A, J = 9.2 Hz, 13.8 Hz), 3.34 (dd, 1H_B, J = 3.8 Hz, 13.8 Hz), 4.73 (dd, 1H, J = 3.8 Hz, 9.2 Hz), 7.24–7.45 (m, 10H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 43.9, 71.8, 126.1, 126.8, 128.1, 128.7, 129.3, 133.2, 138.1. MS, m/z (%): 230 (M⁺, 9), 124 (100), 107 (37), 91 (15), 77 (33).

2-Phenyl-2-(phenylthio)ethan-1-ol, 5

Yellow oil, yield: see Table 2. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 2.02 (br s, 1H), 3.89–3.98 (m, 2H), 4.31 (t, 1H, J = 3.8 Hz), 7.23–7.35 (m, 10H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 55.6, 67.2, 127.3, 127.6, 128.0, 128.5, 128.8, 134.6, 137.4. MS, m/z (%): 230 (M⁺, 43), 199 (78), 121 (97), 110 (99), 103 (76), 91 (100).

(R)-3-(Phenylthio)propane-1,2-diol, 3e

Light yellow oil, yield: see Table 4. ¹H NMR (200 MHz, CDCl₃), δ (ppm): 2.73 (br s, 2H), 2.99 (dd, 1H, J = 7.8 Hz, 13.7 Hz), 3.13 (dd, 1H, J = 4.8 Hz, 13.7 Hz), 3.54–3.63 (m, 2H), 3.73–3.81 (m, 1H), 7.21–7.42 (m, 5H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 37.6, 65.1, 69.9, 126.6, 129.0, 129.2, 134.9. MS, m/z (%): 135 (M⁺, 49,27), 123 (38), 110 (100), 109 (55), 91 (29), 77 (34), 65 (48), 45 (61).

(R)-1-(Phenylthio)-3-[(trimethylsilyl)oxy]propan-2-ol, 4e

Yellow oily liquid, yield: see Table 4. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 0.11 (s, 9H), 1.87 (br s, 1H), 2.88–3.10 (m, 2H), 3.56–3.68 (m, 2H), 3.82–3.87 (m, 1H), 7.24–7.46 (m, 5H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 0.2, 35.3, 65.4, 72.3, 125.9, 128.7, 129.0, 135.5.

2-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylthio)-ethan-1-ol, 3f

Following the general procedure, 1 eq. of d-mannitol epoxide (1f) and 1.2 eq. of the thiosilane 2a were added with 0.6 eq. of TBAF·xH₂O in 0.5 mL of the ionic liquid. Pale yellow oil, yield: see Table 4. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.36 (s, 3H), 1.37 (s, 3H); 1.43 (s, 3H), 1.47 (s, 3H), 2.76 (b s, 1H), 3.19 (app t, 1H, J = 3.6 Hz), 3.72–3.78 (m, 1H), 3.81–3.87 (m, 1H), 3.92–3.96 (m, 1H), 4.06–4.18 (m, 2H), 4.35–4.46 (m, 2H), 7.23–7.44 (m, 5H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 25.4, 25.6, 26.3, 26.8, 54.6, 65.8, 66.5, 67.2, 72.0, 75.4, 109.4, 109.6, 127.0, 129.0, 131.2, 135.3. MS, m/z (%): 354 (M⁺, 10), 339 (8), 281 (6), 236 (9), 123 (12), 110 (16), 109 (14), 101 (100).

1-Isopropoxy-3-(phenylselanyl)propan-2-ol, 14a

Yellow orange oil, yield: see Table 6. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.15 (d, 6H, J = 6.2 Hz), 2.60 (bs, 1H), 3.03 (dd, 1H, J = 12 Hz, 6.6 Hz), 3.10 (dd, 1H, J = 12 Hz, 5.8 Hz), 3.39–3.63 (m, 3H), 3.84–3.96 (m, 1H), 7.21–7.30 (m, 5H). ¹³C NMR (CDCl₃, 50 MHz), δ (ppm): 22.1, 31.9, 69.6, 70.7, 72.2, 126.9, 128.9, 129.7, 132.5. ⁷⁷Se NMR (CDCl₃, 38.1 MHz), δ (ppm): 242.9. MS m/z (%): 274 (M^+·, 26), 272 (11), 201 (8), 183 (30), 158 (31), 99 (59), 73 (48), 57 (100).

[1-Isopropoxy-3-(phenylselanyl)propan-2-yl)oxy]trimethylsilane, 15a

Yellow orange liquid, yield: see Table 6. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 0.10 (s, 9H), 1.12 (b d, 3H, J = 6.4 Hz), 1.14 (b d, 3H, J = 5.8 Hz), 3.01 (dd, 1H, J = 12.7 Hz, 6.4 Hz), 3.17 (dd, 1H, J = 12.7 Hz, 5 Hz), 3.38–3.62 (m, 3H), 3.92–4.15 (m, 1H), 7.21–7.30 (m, 5H). ¹³C NMR (CDCl₃, 50 MHz), δ (ppm): 0.61, 22.3, 32.1, 70.4, 71.1, 73.2, 127.8, 128.2, 130.1, 131.7.

2-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylselanyl)-ethan-1-ol, 14f

Yellow orange liquid, yield: see Table 6. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.35 (s, 6H), 1.38 (s, 3H); 1.46 (s, 3H), 2.86 (b s, 1H), 3.15 (app b t, 1H, J = 4.5 Hz), 3.67–3.78 (m, 1H), 3.88–4.00 (m, 2H), 4.15–4.21 (m, 2H), 4.42–4.53 (m, 2H), 7.26–7.39 (m, 5H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 25.4, 25.6, 26.3, 26.8, 54.6, 65.8, 66.5, 67.2, 72.0, 75.4, 109.4, 109.6, 127.0, 129.0, 131.2, 135.3. MS, m/z (%): 314 (M⁺–88, 29), 312 (20), 310 (13), 234 (17), 232 (8), 157 (62), 155 (30), 154 (34), 153 (19), 77 (100), 51 (76).

3.2.2. General Procedure for the Reaction of Epoxides with bis(trimethylsilyl)sulfide 2b

A mixture of glycidyl isopropyl ether 1a (1 mmol, 116 mg) and HMDST 2b (1.2 mmol) in the ionic liquid (0.4 mL) was stirred at room temperature (when required 0.2 mmol of TBAF·xH₂O was added). The progress of the reaction was followed by TLC (typically: petroleum ether/ethyl acetate 5:1) upon extraction of a small amount with diethyl ether. After completion, the reaction mixture was treated with citric acid (50% aq. solution) and extracted with diethyl ether. The organic phase was then washed with citric acid (20% aq. solution) and dried over Na₂SO₄. Evaporation of the solvent gave the crude product, as variable mixture of β-hydroxy-thiol, -sulfide and -disulfide, which can be purified on silica gel (typically: petroleum ether/ethyl acetate 5:1).

1-Isopropoxy-3-mercaptopropan-2-ol, 7

Yellowish oil, yield: see Table 5. ¹H NMR (200 MHz, CDCl₃), δ (ppm): 1.16 (d, 3H, J = 6.2 Hz), 1.18 (d, 3H, J = 6.2 Hz), 1.48 (app t, 1H, J = 8.8 Hz), 1.93 (b s, 1H), 2.62–2.75 (m, 2H), 3.45–3.67 (m, 3H), 3.74–3.83 (m, 1H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 22.1, 28.2, 70.0, 71.3, 72.2. MS m/z (%): 151 (M⁺+1, 0.3), 117 (6), 99 (28), 91 (11), 73 (35), 61 (22), 57 (100).

3-Isopropoxy-2-[(trimethylsilyl)oxy]propane-1-thiol, 8

Bright yellow oil, yield: see Table 5. ¹H NMR (200 MHz, CDCl₃), δ (ppm): 0.15 (s, 9H), 1.14 (d, 6H, J = 6.0 Hz), 1.4 (b t, 1H, J = 8.4 Hz), 2.46–2.78 (m, 2H), 3.40 (b d, 2H, J = 6.6 Hz), 3.58 (sept, 1H, J = 6.0 Hz), 3.79–3.87 (m, 1H). ¹³C NMR (50 MHz, CDCl₃), δ (ppm): 22.1, 28.2, 70.0, 71.3, 72.2.

3,3′-Thiobis(1-isopropoxypropan-2-ol), 9

Pale yellow oil, yield: see Table 5. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.17 (d, 12H, J = 6.4 Hz), 2.67 (dd, 2H, J = 13.4, 7.2 Hz), 2.77 (dd, 2H, J = 13.4, 4.6 Hz), 3.10 (b s, 2H), 3.39–3.56 (m, 4H), 3.63 (sept, 2H, J = 6.4 Hz), 3.79–383 (m, 2H). ¹³C NMR (CDCl₃, 50 MHz), δ(ppm): 22.1, 36.5, 36.6, 69.7, 69.8, 70.6, 72.3. MS m\z (%): 248 (M⁺–18, 2), 99 (30), 73 (19), 57 (90), 43 (100).

3,3′-Disulfanediylbis(1-isopropoxypropan-2-ol), 11

Pale yellow oil, yield: see Table 5. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.16–1.20 (m, 12H), 2.20 (bs, 2H), 2.82–2.91 (m, 4H), 3.38–3.65 (m, 6H), 3.99–4.07 (m, 2H). ¹³C–NMR (CDCl₃, 50 MHz), δ (ppm): 22.1, 22.2, 42.5, 42.6, 69.4, 69.5, 70.4, 72.3. MS m/z (%): 298 (M⁺, 4), 207 (3), 99 (21), 89 (12), 73 (34), 57 (100).

3.2.3. General Procedure for the Reaction of N-Ts-Aziridine 16 with Silyl Nucleophiles 2a and 13

N-Ts-aziridine 16 (100 mg, 0.42 mmol, 1 eq.) in 0.5 mL of [bmim][BF₄] (or [bmim][PF₆]) was added to 1.1 eq. of PhSSiMe₃ 2a (or PhSeTMS 13) and TBAF·xH₂O (0.2 eq.). The progress of the reaction was followed by TLC (hexanes/ethyl acetate 4:1 or 5:1) upon extraction with diethyl ether of a small amount of the reaction mixture. At the end of the reaction, diethyl ether was added and the organic phase was washed with brine and dried over Na₂SO₄. Evaporation of the solvent afforded the crude product 17 (or 18), which can be purified on silica gel (petroleum ether/ethyl acetate 4:1 or 5:1).

(S)-4-Methyl-N-(3-methyl-1-(phenylthio)butan-2-yl)benzenesulfonamide, 17

Pale yellow solid, yield 45%, [bmim][BF₄]; 40%, [bmim][PF₆]. Recorded spectroscopic data matched those previously reported in the literature [76].

(S)-4-Methyl-N-(3-methyl-1-(phenylselanyl)butan-2-yl)benzenesulfonamide, 18

Yellowish solid, yield 57%, [bmim][BF₄]; 48%, [bmim][PF₆]. Spectroscopic data matched those previously reported in the literature [76].

3.2.4. General Procedure for the Reaction of N-Boc Aziridines with (phenylthio)trimethylsilane 2a and (phenylseleno)trimethylsilane 13

N-Boc-aziridines 19a or 19b (215 and 185 mg, respectively, 1 mmol), in the ionic liquid (0.5 mL), were treated with 1.2 mmoL of PhSSiMe₃ 2a (or PhSeTMS 13). Depending on the used ionic liquid (see Table 7), TBAF·xH₂O (0.24 mmol) or heating were required.

The progress of the reaction was followed by TLC (hexanes/ethyl acetate 4:1 or 5:1) upon extraction with diethyl ether (or chloroform) of a small amount of the reaction mixture. At the end of the reaction, diethyl ether (or CHCl₃) was added (3 × 2 mL) and the organic phase was washed with brine and dried over Na₂SO₄. Evaporation of the solvent afforded the crude product, which can be purified on silica gel (petroleum ether/ethyl acetate 4:1 or 5:1).

tert-Butyl (S)-(4-(methylthio)-1-(phenylthio)butan-2-yl)carbamate, 20a

Pale yellow oil, yield: see Table 7. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.42 (s, 9H), 1.68–1.97 (m, 2H), 2.08 (s, 3H), 2.46–2.55 (m, 2H), 3.12 (b d, 2H, ls = 5.1 Hz), 3.86–3.99 (m, 1H), 4.60–4.63 (b s, 1H), 7.18–7.45 (m, 5H). ¹³C–NMR (CDCl₃, 50 MHz), δ (ppm): 15.1, 28.1, 30.7, 33.4, 39.4, 49.8, 79.8, 126.2, 128.9, 129.6, 135.9, 155.2. MS m/z (%): 327 (M⁺, 5), 254 (4), 218 (9), 211 (5), 204 (11), 148 (32), 124 (25), 104 (51), 57 (100).

tert-Butyl (S)-(4-(methylthio)-1-(phenylselanyl)butan-2-yl)carbamate, 21a

Orange-yellow oil, yield: see Table 7. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.41 (s, 9H), 1.71–1.92 (m, 2H), 2.06 (s, 3H), 2.44–2.53 (m, 2H), 3.11 (b d, 2H, J = 5.4 Hz), 3.83–4.02 (m, 1H), 4.61–4.72 (m, 1H), 7.24–7.88 (m, 3H), 7.48–7.52 (m, 2H). ¹³C–NMR (CDCl₃, 50 MHz), δ (ppm): 15.6, 28.1, 30.4, 32.3, 33.6, 52.4, 79.3, 126.9, 129.0, 132.3, 155.2. ⁷⁷Se NMR (CDCl₃, 38.1 MHz), δ (ppm): 239.9. MS m\z (%): 375 (M⁺, 2), 259 (4), 162 (25), 118 (26), 91 (11), 70 (22), 61 (54), 57 (100).

tert–Butyl (S)–(3–methyl–1–(phenylthio)butan–2–yl)carbamate, 20b

Yellowish oil, yield: see Table 7. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 0.90 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J = 6.8 Hz), 1.43 (s, 9H), 1.92 (app sext, 1H, J = 6.8 Hz), 3.07 (b d, 2H, J = 5.6 Hz), 3.59–3.71 (m, 1H), 4.52–4.60 (m, 1H), 7.17–7.53 (m, 5H). ¹³C–NMR (CDCl₃, 50 MHz), δ (ppm): 19.4, 19.6, 28.4, 30.9, 37.7, 55.3, 79.2, 126.1, 127.4, 128.9, 136.9, 156.1. MS m/z (%): 295 (M⁺, 4), 179 (4), 172 (17), 152 (3), 135 (5), 123 (17), 116 (36), 110 (6), 72 (70), 57 (100).

tert–Butyl (S)–(3–methyl–1–(phenylselanyl)butan–2–yl)carbamate, 21b

Yellow oil, 47% yield. ¹H and ¹³C NMR data matched those previously reported in the literature. [76]. ⁷⁷Se NMR (CDCl₃, 38.1 MHz), δ (ppm): 244.1.

3.2.5. Reaction of Aziridine 19a with bis(trimethylsilyl)sulfide 2b

A mixture of N–Boc–aziridine 19a (215 mg, 1 mmol) in the ionic liquid (0.5 mL) and HMDST (1.2 mmoL) was added to TBAF·xH₂O (0.24 mmol) and stirred at room temperature. The progress of the reaction was followed by TLC (hexanes/ethyl acetate 5:1) upon extraction with diethyl ether of a small amount, and, after completion, the reaction mixture was treated with citric acid (50% aq. solution) and extracted with diethyl ether. The organic phase was then washed with citric acid (20% aq. solution) and dried over Na₂SO₄. Evaporation of the solvent gave the crude product, which was purified on TLC (petroleum ether/ethyl acetate 5:1) to afford β–amino–disulfide 22 (major) and β–amino–thiol 23 (minor).

di–tert–Butyl [(2S,2′S)–disulfanediylbis(4–(methylthio)butane–1,2–diyl)]dicarbamate, 22

Yellow oil, yield: see Table 8. ¹H NMR (CDCl₃, 400 MHz), δ (ppm): 1.44 (s, 18H), 1.66–1.75 (m, 4H), 1.85–1.94 (m, 2H), 2.11 (s, 6H), 2.48–2.58 (m, 4H), 2.68 (dd, 2H, J = 13.2 Hz, 6 Hz), 2.75 (dd, 2H, J = 13.2 Hz, 5.8 Hz), 3.78–3.90 (m, 2H), 4.64–4.72 (m, 2H). ¹³C NMR (CDCl₃, 50 MHz), δ (ppm): 15.3, 28.4, 30.7, 33.6, 38.2, 49.6, 79.6, 155.3. MS m/z (%): 351 (M⁺–149, 3), 250 (5), 194 (11), 162 (10), 148 (16), 104 (34), 101 (40), 57 (100).

tert–Butyl (S)–(1–mercapto–4–(methylthio)butan–2–yl)carbamate, 23

Yield: see Table 8. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 1.31 (t, 1H, J = 8.8 Hz, SH). Most of the other proton signals are overlapped with those of the disulfide 22. ¹³C NMR (CDCl₃, 50 MHz), δ (ppm): 15.6, 28.4, 29.5, 30.7, 32.6, 50.9, 79.6, 155.4.

3.2.6. General Procedure for the Ring Opening of Thiiranes 24

Thiirane 24 (100 mg, 0.76 mmol) in 0.4 mL of the appropriate ionic liquid were treated with (phenylthio)trimethylsilane 2a (1.2 eq.) or (phenylthio)trimethylsilane 13 (1.2 eq.). Depending on the ionic liquid, TBAF·xH₂O (0.24 mmol) was added (see Table 9). Progress of the reaction was monitored by TLC (hexanes:ethyl acetate 7:1). At the end, the reaction mixture was treated with citric acid (50% aq. solution) and extracted with diethyl ether. The organic phase was washed with citric acid (20% aq. solution) and dried over Na₂SO₄. Evaporation of the solvent gave the crude product, as mixture of products (25, 26, 27 and 28, 29), which can be purified on silica gel (petroleum ether:ethyl acetate).

1–Isopropoxy–3–(phenylthio)propane–2–thiol, 25

Yellow oil, yield: see Table 9. NMR signals partially overlapped with disulfide 26. ¹H NMR (CDCl₃, 400 MHz), δ (ppm): 1.13 (d, 6H, J = 6.0 Hz), 2.11 (d, 1H, J = 7.9 Hz), 3.13–3.34 (m, 3H), 3.41–3.46 (m, 1H), 3.53 (dd, 1H, J = 9.2 Hz, 5.2 Hz), 3.66 (dd, 1H, J = 9.2 Hz, 4.8 Hz), 7.20–7.43 (m, 5H). ¹³C NMR (CDCl₃, 50 MHz), δ (ppm): 22.1, 39.4, 39.9, 70.8, 72.2, 126.2, 128.8, 129.5, 135.7. MS m/z (%): 242 (M⁺, 31), 149 (5), 123 (12), 109 (26), 73 (23), 57 (100).

1,2–Bis(1–isopropoxy–3–(phenylthio)propan–2–yl)disulfane, 26

Yellow oil, yield: see Table 9. NMR signals partially overlapped with thiol 25. ¹H NMR (CDCl₃, 400 MHz), δ (ppm): 1.15 (d, 12H, J = 6.2 Hz), 2.82–3.12 (m, 6H), 3.56–3.75 (m, 6H); 7.22–7.54 (m, 10H). ¹³C NMR (CDCl₃, 50 MHz), δ (ppm): 22.1, 39.5, 41.4, 69.7, 72.0, 126.2, 128.8, 129.5, 135.7. MS m/z (%): 405 (M⁺–77, 4), 328 (11), 273 (19), 242 (100), 196 (24), 142 (21), 99 (22), 73 (20), 57 (44).

1–Isopropoxy–3–(phenylselanyl)propane–2–thiol, 28

Not isolated (see Table 9), characteristic data. ¹H NMR (CDCl₃, 200 MHz), δ (ppm): 2.18 (d, 1H, J = 8.0 Hz, SH). The other signals are overlapped with the disulfide 29.

1,2–Bis(1–isopropoxy–3–(phenylselanyl)propan–2–yl)disulfane, 29

Pale orange oil, yield: see Table 9. ¹H NMR (CDCl₃, 200 MHz), δ (ppm): 1.15–1.25 (m, 12H), 2.99–3.29 (m, 6H), 3.43–3.77 (m, 6H), 7.23–7.61 (m, 10H). ¹³C NMR (CDCl₃, 50 MHz), δ (ppm): 22.0, 35.6, 39.7, 71.1, 72.5, 127.8, 128.2, 130.9, 134.2. ⁷⁷Se NMR (CDCl₃, 38.1 MHz), δ (ppm): 282.8, 284.9.

4. Conclusions

In conclusion, we have found that the ring opening of strained heterocycles by thiosilanes and selenosilanes can be efficiently carried out in various RTILs. Thus, ionic liquids are able to act as alternative reaction media, and in some cases also as catalysts. This synthetic protocol allows the preparation of β–disubstituted sulfides and selenides bearing different substituents such as hydroxyl, N–Ts or N–Boc amino, and sulfurated groups under mild conditions with high regiocontrol.